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Abnormal intrinsic and extrinsic connectivity within the magnetic mismatch negativity brain network in schizophrenia: a preliminary study

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Dima, D., Frangou, S., Burge, L., Braeutigam, S. and James, A. C. (2012). Abnormal intrinsic and extrinsic connectivity within the magnetic mismatch negativity brain network in schizophrenia: a preliminary study. Schizophrenia Research, 135(1-3), pp. 23-27. doi: 10.1016/j.schres.2011.12.024

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Elsevier Editorial System(tm) for Schizophrenia Research Manuscript Draft

Manuscript Number: SCHRES-D-11-00698R2

Title: Abnormal intrinsic and extrinsic connectivity within the magnetic mismatch negativity brain network in schizophrenia: a preliminary study

Article Type: Brief Report

Keywords: dysconnection syndrome; dynamic causal modelling; experience dependent modulation; connectivity; error prediction; mismatch negativity

Corresponding Author: Dr. Danai Dima, Ph.D.

Corresponding Author's Institution: Institute of Psychiatry (PO66) First Author: Danai Dima, Ph.D.

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Title: Abnormal intrinsic and extrinsic connectivity within the magnetic mismatch negativity brain network in schizophrenia: a preliminary study.

Authors: Dima D1*, Frangou S1, Burge L2, Braeutingam S3, James A2,4

1. Section of Neurobiology of Psychosis, Department of Psychosis Studies, Institute

of Psy hiatry, King’s College London, De Crespigny Park, London SE5 8AF, UK

2. Highfield Adolescent Unit, Warneford Hospital, Oxford OX3 7JX, UK

3. Oxford Centre for Human Brain Activity, Warneford Hospital, Oxford OX3 7JX, UK 4. Oxford University, Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK

*

Corresponding author:

Dr. Danai Dima, Section of Neurobiology of Psychosis, Department of Psychosis Studies, Institute of Psychiatry (PO66), King’s College London, De Crespigny Park, London SE5 8AF, UK. E-mail: danai.dima@kcl.ac.uk; Tel: +44 2078480425; Fax: +44 2078480983

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Abstract

Altered neuroplasticity is increasingly invoked as a mechanism underpinning dysconnectivity in schizophrenia. We used Dynamic Causal Modelling to compare

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1. Introduction

The auditory Mismatch Negativity (MMN) is a neuronal response time-locked to the presentation of a novel (oddball) stimulus embedded within a train of repeated

(standard) stimuli. According to the adaptation theory, the standard stimuli produce experience-dependent adaptation in feature-specific neurons against which incoming stimuli are contrasted. The oddball stimulus elicits a neural mismatch response compared to this sensory memory trace (Näätänen et al., 1999). The

adjust ent odel hypothesis introdu es the notion of a supra odal ’’ odel’’ of the

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between (extrinsic) these regions relating to prediction errors elicited by oddball stimuli (Garrido et al., 2008). As the MMN indexes experience-dependent changes in connectivity within cortical circuits there is renewed interest in this paradigm as a sensitive, non-invasive pro e of neuroplasti ity Baldeweg et al., 2006).

Neuroplasticity can be conceptualized in different ways, but as used here it refers to altered functional coupling within cortical circuits as a function of experience (Stephan et al., 2009a). Altered neuroplasticity is increasingly invoked as a mechanism underpinning dysconnectivity in schizophrenia (Bullmore et al., 1997; Stephan et al., 2009a). It is therefore noteworthy that deficient MMN is a robust finding in schizophrenia which also shows evidence of disease specificity (Javitt et al., 2008).

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2.Methods and Materials

2.1 Subjects

Fourteen patients fulfilling Diagnostic and Statistical Manual of Mental Disorders -

Fourth Edition (DSM-IV) (APA, 1994) criteria for schizophrenia were recruited from the Highfield Adolescent Unit, Warneford Hospital, Oxford and were matched to twelve healthy volunteers who had no personal history of psychiatric disorder and no history of psychosis in their first-degree relatives (Table 1). Details of recruitment and assessment are shown in Supplementary Material. The study was approved by the Berkshire Research Ethics Committee. All participants and their parents or guardians, as appropriate, provided written informed consent.

2.2 Experimental design

We used an auditory roving odd all’ paradig developed and validated by Garrido et al. (2008) and described in detail in Supplementary Material.

2.3 MEG acquisition and analysis

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2.4 Dynamic causal modelling

We specified 3 models: (a) Forward model, according to the adaptation hypothesis, (b) Backward model, according to the adjustment hypothesis, and (c) Combination

model according to the framework of predictive coding (Figure 1). All models were constructed, fitted and compared for each of the participants as described in detail in Supplementary material.

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3. Results

3.1 MMN results

The grand average ERF to standard and oddballs for each group are illustrated in

Figure 2A and 2B. Significant group differences were found in the MMN time window 150 to 360 ms over frontal and central areas (Figure 2C; Figure 3).

3.2 Model comparison

As anticipated (Garrido et al., 2008) in healthy controls the Combination model outperformed both the Forward and Backward models with exceedance probability of 89%. The Combination model assumes that the MMN response emerged from changes in all bidirectional extrinsic as well as in intrinsic connections. In patients the optimal model included modulation via the MMN of the intrinsic connections and only the forward connections, which was the Forward model. The exceedance probability for this model was 44%, surpassing the exceedance probabilities of the other two tested models.

3.3 MMN modulatory parameters

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4. Discussion

4.1 Abnormal intrinsic and extrinsic connectivity in temporal lobe sources during

MMN generation in schizophrenia

During the roving paradigm each oddball tone is repeated after its first presentation thus becoming a standard tone. In healthy individuals this transition is associated with neuroplastic changes resulting in increased intrinsic connectivity within A1 and in extrinsic connectivity to the STG. Intrinsic changes reflect local neuronal adaptation that relates to concepts of sensory memory and extrinsic changes are considered relevant to sensory learning (Garrido et al., 2009).

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sensory to secondary association areas. Accordingly patients showed reduced modulation of the forward connection from the A1 to the STG. The STG is considered a key node for the early detection of auditory mismatches and the strength of the connectivity between from A1 to STG normally increases when the auditory input

does not match predictions (Gariddo et al., 2009). Taken together our results point to deficits in sensory memory formation leading to inefficient processing of auditory information within primary auditory cortices and reduced precision in error.

4.2 Abnormally increased backward frontotemporal connectivity during MMN

generation in schizophrenia

In healthy individuals, the backward connection from the IFG to the STG during the MMN shows a negative modulation which has been interpreted as an inhibitory effect relating to suppression of the prediction error (Garrido et al., 2009). In patients this inter-regional coupling was increased and showed reverse (positive) polarity. This resonates with the findings by Winterer et al. (2003) who also observed a negative frontotemporal path coefficient in normal controls and a positive in patients with schizophrenia. This positive modulation in patients is suggestive of a loss of higher-order signals disambiguating activity in lower areas.

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4.3 Implications for neuroplasticity and dysconnectivity in schizophrenia

Our findings provide the first empirical description of the dysplastic changes underpinning dysconnectivity between primary sensory and higher order cortical

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References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association, Washington, D.C. 1994.

Baldeweg, T., Klugman, A., Gruzelier, J., Hirsch, S.R., 2004. Mismatch negativity potentials and cognitive impairment in schizophrenia. Schizophr. Res. 69, 203–217.

Baldeweg, T., 2006. Repetition effects to sounds: evidence for predictive coding in the auditory system. Trends Cogn. Sci. 10, 93–94.

Bullmore, E.T., Frangou, S., Murray, R.M., 1997. The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia. Schizophr. Res. 28, 143–156.

Cohen, J., 1988. Statistical power analysis for the behavioral sciences, second ed. Lawrence Earlbaum Associates Hillsdale, New York.

Dima, D., Dietrich, D.E., Dillo, W., Emrich, H.M., 2010. Impaired top-down processes in schizophrenia: A DCM study of ERPs. NeuroImage 52, 824-832.

Dima, D., Roiser, J.P., Dietrich, D.E., Bonnemann, C., Lanfermann, H., Emrich, H.M., Dillo, W., 2009. Understanding why patients with schizophrenia do not perceive the hollow mask illusion using dynamic causal modelling. NeuroImage 46, 1180-1186.

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Friston, K.J., 2005. Models of brain function in neuroimaging. Annu. Rev. Psychol. 56, 57–87.

Garrido, M.I., Friston, K.J., Kiebel, S.J., Stephan, K.E., Baldeweg, T., Kilner, J.M., 2008. The functional anatomy of the MMN: a DCM study of the roving paradigm.

NeuroImage 42, 936–944.

Garrido, M.I., Kilner, J.M., Stephan, K.E., Friston, K.J., 2009. The mismatch negativity: a review of the underlying mechanisms. Clin. Neurophysiol. 120, 453–463.

Javitt, D.C., Spencer, K.M., Thaker, G.K., Winterer, G., Hajos, M., 2008. Neurophysiological biomarkers for drug development in schizophrenia. Nat. Rev. Drug Discov. 7, 68–83.

Meyer-Lindenberg, A., Poline, J.B., Kohn, P.D., Holt, J.L., Egan, M.F., Weinberger, D.R., Berman, K.F., 2001. Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. Am. J. Psychiat. 158, 1809–1817.

Näätänen, R., Kähkönen, S., 2009. Central auditory dysfunction in schizophrenia as revealed by Mismatch Negativity and its magnetic equivalent mMMN: a review. Int. J. Neuropsychopharmacol. 12, 125-135.

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Stephan, K.E., Penny, W.D., Daunizeau, J., Moran, R.J., Friston, K.J., 2009b. Bayesian model selection for group studies. NeuroImage 15, 1004-1017.

Umbricht, D., Krljes, S., 2005. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr. Res. 76, 1-23.

Wible, C.G., Kubicki, M., Yoo, S.S., Kacher, D.F., Salisbury, D.F., Anderson, M.C., Shenton, M.E., Hirayasu, Y., Kikinis, R., Jolesz, F.A., McCarley, R.W., 2001. A functional magnetic resonance imaging study of auditory mismatch in schizophrenia. Am. J. Psychiatry 158, 938–943.

Winkler, I., Karmos, G., Näätänen, R., 1996. Adaptive modelling of the unattended acoustic environment reflected in the mismatch negativity event-related potential. Brain Res. 742, 239–252.

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Figure Legends

Figure 1. Model specification: The sources comprising the models were: A1: primary

auditory area; STG: superior temporal gyrus; IFG: inferior frontal gyrus; L: left; R:

right. Three models with five areas were specified with bidirectional endogenous

connections between all regions (L_A1, R_A1, L_STG, R_STG, R_IFG), intrinsic

connections in the A1s and with driving input of standard and odd all tones’ into

the A1 bilaterally. Schematically, the modulation MMN is represented as dashed

lines in the bidirectional endogenous connections and as grey colour in the intrinsic

connections. The three models are: (i) Combination model that has all connections

modulated, (ii) Forward model that has the intrinsic and forward connections

modulated and (iii) Backward model that had the intrinsic and backward connections

modulated.

Figure 2. A. Grand average ERF waveforms for standard and oddball tones in the

patient group (n=14) for a MEG channel corresponding broadly to Cz location. B.

Grand average ERF waveforms for standard and oddball tones in the controls group

(n=12) for the same channel. C. MMN waveforms (standard minus oddball tones) for

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space and all peri-sti ulus ti es −1 to 4 s . Significant effects were found

over temporal and frontal areas in the range 110 to 320 ms peaking at around 200

ms. B. Difference topographic maps of the MMN waves (standard minus oddball

tones) for controls minus patients.

Figure 4. Mean coupling changes (BMA, averaged across subjects in each group) lie

beside the connections in the graph for healthy controls and patients. A1: primary

auditory area; STG: superior temporal gyrus; IFG: inferior frontal gyrus; L: left; R:

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Acknowledgements

The authors wish to thank the participants and their families for their help with the

study. We thank Marta Garrido for providing the roving oddball paradigm.

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Conflict of Interest

The authors declare that they have no conflicts of interest.

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Contributors

Drs Dima, Braeutigam, Frangou and James were involved in the conceptualisation of

the study. Dr. Braeutigam adapted the roving oddball paradigm for MEG. Drs. Dima,

Braeutigam, Burge and James performed patient recruitment and data collection. Dr.

Dima and Dr. Frangou conducted the data analysis and wrote the first draft of the

manuscript, which was edited by Drs. Braeutigam and James. All authors contributed

to and have approved the final manuscript.

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Figure(s)

[image:21.792.40.753.114.508.2]
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[image:22.792.67.757.46.533.2]

Figure 2

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[image:23.792.58.734.37.548.2]

Figure 3

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[image:24.792.478.748.52.411.2]

Figure 4

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Role of the funding source

This study was supported by the Medical Division of Oxford University. The Medical

Division had no further role in study design; in the collection, analysis and

interpretation of data; in the writing of the report; and in the decision to submit this

paper for publication.

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Table 1: Demographics and psychopathology data. Patients N=14 Controls N=12 Statistics

Male:Female 8:5 5:7 Fisher’s e act test, p=0.

Age 17.1 (0.9) 16.2 (1.9) t = 1.65; p = 0.112

Handedness R:L 13:1 10:2 Fisher’s e act test, p=0.

WASI IQ 96 (15) 112 (9) t = 2.44; p = 0.027

Positive PANSS score 22.1 (3.6)1 - -

Negative PANSS score 12.57 (5.5)2 - -

General PANSS score 34.7 (5.1)3 - -

Age of onset (in years) 16.2 (1.2) - -

Duration of illness (years) 1.01 (0.95) - -

Medication (mg/day; CPZE) 275 (95) - -

For continuous variables data shown are mean (standard deviation);

PANSS= Positive and Negative Syndrome Scale; WASI= Wechsler Abbreviated Scale of Intelligence;

CPZE= chlorpromazine equivalents;

1

Positive PANSS scale range: 16-29; 2Negative PANSS scale range: 7-30; 3General PANSS scale range:

[image:26.595.90.550.112.476.2]

27-47

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Table 2. Mean (standard deviations) BMA MMN modulatory estimates for all connections across the three models in the controls and patients group.

Connection type Healthy Controls (n=12) Patients with Schizophrenia (n=14) Absolute effect size of the BMA differences between patients and controls

P-values

MMN Modulatory parameters

LA1 0.066 (0.115) 0.019 (0.064) 0.54 0.20

RA1 0.117 (0.078) 0.029 (0.108) 0.96 0.02

LA1→LSTG -0.011 (0.295) -0.018 (0.198) 0.03 0.94

RA1→RSTG -0.171 (0.236) -0.033 (0.280) 0.55 0.18

LSTG→LA1 0.061 (0.257) -0.047 (0.358) 0.36 0.37

RSTG→RA1 0.026 (0.242) 0.003 (0.321) 0.08 0.83

RSTG→RIFG -0.055 (0.180) -0.037 (0.214) 0.09 0.82

RIFG→RSTG -0.081 (0.118) 0.066 (0.222) 0.84 0.04

BMA=Bayesian Model Average; MMN=Mismatch Negativity; Relative size of Cohen’s d (Cohen, 1988):

negligible effect (>= -0.15 and < 0.15), small effect (>= 0.15 and < 0.4), medium effect (>= 0.4 and <

[image:27.595.89.515.157.583.2]

0.75) and large effect (>= 0.75 and < 1.10)

Figure

Figure(s)Click here to download high resolution image
Figure 2Click here to download high resolution image
Figure 3Click here to download high resolution image
Figure 4Click here to download high resolution image
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